Endotoxic hepatotoxicity in rats is exacerbated by tacrolimus and diminished by cyclosporine or sirolimus: modulation by androgenic hormones

Liver toxicity contributes to poor prognosis and increased mortality rate in septic and endotoxic patients. Given the discrepant hepatic influences of immunosuppressant therapies, biochemical and histopathological studies were performed to determine whether endotoxic hepatotoxicity is variably altered by calcineurin‐dependent (cyclosporine and tacrolimus) and independent immunosuppressant (sirolimus) in rats. The data showed that 6‐hr treatment of rats with lipopolysaccharide (LPS, 3 mg/kg i.p.) significantly increased serum levels of serum glutamic pyruvic transaminase (sGPT) and glutamic oxaloacetic transaminase (sGOT). Morphologically, livers of endotoxic rats showed evidence of portal tract inflammation, neutrophil infiltration, central vein congestion, and focal lytic necrosis. Except for mild portal inflammation and congestion, these hepatic anomalies were largely compromised in endotoxic rats pretreated 2 hr earlier with cyclosporine (10 mg/kg i.p.) or sirolimus (1 mg/kg i.p.). By contrast, the prior exposure to tacrolimus (2 mg/kg i.p.) accentuated hepatotoxic manifestations of endotoxemia as indicated by the significant elevations in serum sGPT and sGOT beyond endotoxic levels and loss of regular cord arrangement of hepatocytes, apparent bile secretion within bile canaliculi, hemorrhagic areas, cytoplasmic vacuolization, and marked congestion. We also show that functional androgenic pathways seem necessary for the demonstration of hepatotoxic manifestations caused by LPS or its combination with tacrolimus because such effects were remarkably attenuated in rats with surgical (castration) or pharmacologic (flutamide, androgen receptor blocker) testosterone depletion. Our data indicate that immunosuppressants exhibit diverse, calcineurin‐independent, testosterone‐mediated effects on endotoxic hepatotoxicity in male rats.